Ingenol-3-angelate (PEP005, ingenol mebutate, Picato®) is a diterpene-ester of the ingenol family which is isolated from various Euphorbia species, particularly from Euphorbia peplus. The compound has been launched for the treatment of actinic keratosis and is presently subject for clinical development for non-melanoma skin cancer.
WO99/08994 describes isolation of compounds from Euphorbia plant and their use in cancer and other neoplastic diseases hereunder actinic keratosis or solar keratosis.
WO 2012/085189, WO 2012/083954 and WO 2012/083953 describe ingenol-3-acylates and ingenol-3-carbamates which stimulate neutrophil oxidative burst, stimulate keratinocyte IL-8 release or which induce rapid necrosis.
Sorg et. al. Z Naturforsch. 37b, 1640-7 (1982) has described 3-O-(2-methoxyethoxyl)methyl-ingenol as an intermediate in the preparation of ingenol derivatives.
Ingenol-3-angelate is believed to have a dual mode of action: 1) Induction of cell death by direct cytoxicity or induction of apoptosis and 2) an immunostimulatory effect dominated by neutrophil recruitment and activation (Rosen, R. H., et al., J Am Acad Derm (2012), 66, 486-493; Ersvaer, E., et al., Toxins, (2010), 2, 174-194). Nanomolar concentrations of the agent cause activation and modulation of protein kinase C (PKC) classical and novel isoforms, with particular importance of PKCdelta. Through activation of PKCdelta the agent induces apoptosis in susceptible cells (Hampson, P., et al., Blood, (2005), 106, 1362-1368; Cozzi, S. J., et al., Cancer Res, (2006), 66, 10083-10091). Rapid cytotoxicity on cancer cells is observed at high micromolar concentrations (Ogbourne, S. M., et al., Cancer Res (2004), 64, 2833-2839). Through activation of various PKC isoforms the agent also induces pro-inflammatory effects, including release of pro-inflammatory mediators (Challacombe, J. M., et al., J Immunol (2006), 177, 8123-8132, activation of vascular endothelium (Hampson, P., et al., Cancer Immunol Immunother, (2008), 57, 1241-1251); chemoattraction of neutrophils through induction of interleukin 8 in keratinocytes and development of specific anti-cancer immune responses by CD8+ cells through adjuvant properties in animal models (Le, T. T., et al., Vacccine, (2009), 27, 3053-3062).
Compounds exerting dual mode of action by induction of cell death by direct cytoxicity or induction of apoptosis, and by an immunostimulatory effect involving neutrophil recruitment and activation, may be useful for treatment of conditions associated with hyperplasia, neoplasia or dysplasia. Compounds inducing cell death by primary and/or secondary necrosis and compounds exhibiting a pro-apoptotic effect may reduce unwanted cell growth and remove unwanted cells, and furthermore, stimulation of the innate immune response and adjuvant effects may augment the biological response against aberrant or transformed cells.
Compounds inducing cell death by primary and/or secondary necrosis may be useful for treatment of cosmetic conditions, as these compounds may kill or remove unwanted tissue or cells.
There is a continuous need to find new ingenol derivatives which induce cell death by cytotoxicity or apoptosis and/or induce an immunostimulatory effect.